The present invention relates to a method and an adjunct or complement composition to traditional therapies for the treatment or prevention of prostate cancer in mammals as well as a method and composition useful for the prevention of the onset of prostate cancer in mammals. The composition of this invention comprises of Vitamin E or a Vitamin E derivative in combination with selenium either in combined or uncombined form in amounts which provide preventive and therapeutic effects with mammalian prostate carcinoma.
Prostate cancer is the most common cancer in mammals, especially among human males in North America, and it is the second leading cause of cancer death in men in the Western countries. See Parker S I, et al, xe2x80x9cCancer Statistics 1997,xe2x80x9d CA Cancer J Clin (1997) 47:5-27. Various factors such as an unknown etiology, variable pathology, an intricate relationship to endocrine factors, and anaplastic progression contribute to the complexity of this disease.
Evidence from epidemiologic, clinical and laboratory studies supports the concept that a complex interaction between the host antioxidant defense system and dietary antioxidants may participate in the origin and progression of prostate cancer, as well as other forms of cancer. For example, supplemental consumption of the antioxidant Vitamin E has been associated with a reduction of about one-third in mortality from prostate cancer. See, e.g., Fleshner N E, xe2x80x9cVitamin E Inhibits the High-Fat Diet Promoted Growth of Established Human Prostate LNCaP Tumors in Nude Mice,xe2x80x9d J Urol (1999) 161: 1651-1654. Considerable interest has also been generated in the possible role of trace elements in cancer prevention and intervention. An indirect correlation between the levels of bioavailable selenium in the human environment and cancer mortality has also been reported. See Hunter D J, Morris J S, Stampfer M J et al., xe2x80x9cA Prospective Study of Selenium Status and Breast Cancer Risk,xe2x80x9d JAMA (1990) 264: 1128-1131; See Van den Brandt P A, Goldbohn R A, Bode P et al., xe2x80x9cA Prospective Study on Toenail Selenium Levels and Risk of Gastrointestinal Cancer,xe2x80x9d J Natl Cancer Inst (1993) 85: 224-229; See Van Den Brandt P A, Goldbohn R A, Bode P et al., xe2x80x9cA Prospective Study On Selenium Status And The Risk Of Lung Cancer,xe2x80x9d Cancer Res (1993) 53: 4860-4865; See Helzlsouer K J, Comstock G W, Morris J S et al., xe2x80x9cSelenium, Lycopene, A-Tocopherol, B-Carotene, Retinol and Subsequent Bladder Cancer,xe2x80x9d Cancer Res (1989) 49: 6144-6148; See Willett We, Polk B F, Morris J S et al, xe2x80x9cPrediagnostic Serum Selenium and Risk of Cancer,xe2x80x9d Lancet (1983) 2: 130-134; See Levander O A, xe2x80x9cScientific Rationale for the 1989 Recommended Dietary Allowance for Selenium,xe2x80x9d Perspect Pract (1991) 91: 1572-1576. Accumulating evidence suggests that in many models of experimental carcinogenesis, supplementation of the diet with sodium selenite results in a decrease in the incidence of chemical carcinogen-induced carcinomas. See Heinonen O P, et al., xe2x80x9cProstate Cancer and Supplementation with Alpha-Tocopherol and Beta-Carotene: Incidence and Mortality in a Controlled Trial,xe2x80x9d J Natl Cancer Inst. (1998) 90: 440-446.
Epidemiological data and prior research therefore suggests that micronutrient ingestion and diet play a pivotal role in prostate carcinogenesis. Androgen has also been shown to contribute to prostate carcinogenesis. See Ripple M O, et al., xe2x80x9cProoxidant-Antioxidant Shift Induced by Androgen Treatment of Human Prostate Carcinoma Cells,xe2x80x9d J Natl Cancer Inst. (1997) 89: 40-48. The link between diet and the androgens may be oxidative stress. This process is caused by a host of reactive oxygen species which can trigger carcinogenesis. Previous research has found that exogenous androgen increases oxidative stress in human prostate cancer cell lines. See Fleshner, J Urol. (1995) 161: 1651-1654.
The cell cycle clock orchestrates the progression of cells through growth and division cycles. Thus it determines whether a cell continues its proliferation or withdraws and enters a state of quiescence. Thus, DNA replication and mitosis are controlled by the activation of S phase- and M phase-specific cyclin-dependent protein kinases (CDKs), respectively. The catalytic subunits of CDKs are active only when complexed with their specific regulatory subunits, termed cyclins. The CDKs control the various cellular processes through phosphorylation of the appropriate substrates within the cell. See Solomon M J, xe2x80x9cActivation of the Various Cyclin/cdk2 Proteins,xe2x80x9d Curr. Opin. Cell Biol. (1993) 5: 180-186. The cyclins guide, bind and direct CDKs to appropriate substrates during various phases of the cell cycle thereby dictating where and when these substrates will become phosphorylated. See Hartwell L, xe2x80x9cDefects in a Cell Cycle Checkpoint May Be Responsible for the Genomic Instability of Cancer Cells,xe2x80x9d Cell (1992) 71: 543-546. Other important components are the CDK inhibitors (CKIs), such as p21 and p27, that block the action of specific cyclin-CDK complexes. This prevents cell proliferation thus forcing it to enter a state of quiescence, called the G0 phase. See Sherr C J et al, Genes Dev. (1999) 13: 1501-1512.
Uncontrolled cell proliferation is the hallmark of cancer. Tumor cells contain or acquire damaged genes that directly regulate their cell cycle. Like other types of cancer, prostate cancer is associated with loss of cell cycle control, resulting in unregulated growth of cells. The precise mechanism by which this occurs is still unknown. See La Thangue N B, xe2x80x9cIntroduction: Cell Cycle Regulation and Cancer,xe2x80x9d Seminars in Cancer Biol. (1995) 6: 61-62. Cell cycle arrest is mediated by the CKIs p27 and p21. See Tslhlias J et al, xe2x80x9cInvolvement of p27Kip1 in G1 Arrest by High-Dose 5xcex1-Dihydrotestosterone in LNCaP Human Prostate Cancer Cells,xe2x80x9d Oncogenes (2000) 19: 670-679.
The basis of cell cycle control machinery is comprised of regulatory cyclin subunits complexed to catalytic serine/threonine CDK subunits that phosphorylate substrates in a cell cycle specific fashion. See, e.g., Morgan D O, xe2x80x9cCyclin-Dependent Kinases: Engines, Clocks and Microprocessors,xe2x80x9d Ann. Rev. Dev. Biol. (1997) 13: 261-291. Activation of CDK2 by cyclin E in late G1 at/near the G1 restriction point and by cyclin A at the G1-S phase transition, and cyclin B activation of CDK2 at the G2/M phase transition, suggests the involvement of these cyclin-CDK complexes at specific cell cycle regulatory checkpoints. Id. It is known that p21, a cyclin-dependent kinase inhibitor, can induce cell cycle arrest in G1 and/or G2 by inhibiting kinase activity. Additionally, p27 is regulated by a number of mitogenic and growth inhibitory cytokines and by contact inhibition. See Polyak C et al., xe2x80x9cp27Kip1, a Cyclin-cdk Inhibitor, Links Transforming Growth Factor-xcex2 and Contact Inhibition to Cell Cycle Arrest,xe2x80x9d Genes Dev. (1994) 8: 9-22. Although growth arrest is not always associated with increased p27 protein levels, id., it is an important mediator of G1 arrest because it acts during G0 and early G1 phase of the cell cycle and inhibits cyclin D1-CDK4 and cyclin E-CDK2 complexes. See Pagano M et al., xe2x80x9cRole of Ubiquitin-Proteasome Pathway in Regulating Abundance of the Cyclin-Dependent Kinase Inhibitor p27,xe2x80x9dScience (1995) 269: 682-685.
Although the anti-carcinogenic effects of Vitamin E and selenium have been noted and studied, there has not been a disclosure for the use of a combination of these two materials for the prevention and/or treatment of mammalian prostate carcinoma. Furthermore, while there are other agents available for chemotherapy of tumors, and other invasive treatment options exist for prostate cancer such as removal of the cancerous prostate or placement of a radioactive seed designed to shrink the tumor, it would be more desirable to provide a composition useful as an adjunct or complement to traditional therapies of low toxicity to a patient which will serve as an anti-carcinogenic agent, especially for prostate cancer. Alternatively, it is desirable to provide compositions which increase levels of p21 and/or p27, as well as other CDK-inhibitors to prevent and treat prostate cancer in mammals.
An object of this invention is to provide a composition and method which may be used to treat or prevent prostate carcinoma in mammals.
A further object of this invention is to provide a composition comprising Vitamin E or Vitamin E derivatives or Vitamin E analogs and selenium or a selenium salt or selenium derivative in uncombined or combined form in which this composition exhibits enhanced anticarcinogenic properties, especially for the prevention or treatment of mammalian prostate carcinoma.
Another object of the invention is to provide a method and an adjunct or complement composition to traditional therapies for the treatment or prevention of the onset of prostate cancer in mammals.
A still further object of this invention is to provide a method and a composition which inhibit the formation of cyclin-CDK protein complexes, via p21 or p27 upregulation, for the prevention and treatment of mammalian prostate carcinoma.